A Na transport inhibitory mechanism, previously undescribed, has been established in frog skin. It is mediated by alteration in conductance or permeability of the passive co-ion, chloride, and is responsive to preconditioning of the animals in high concentration of NaCl. A humoral agent (s) probably responsible for the adaptive changes has been demonstrated in the frog. Change in chloride flux in short- circuited isolated frog skin (Cl conductance) and change in Na flux in open- circuit skins was used to detect this factor. Plasma from frogs, appropriately pre-conditioned, will be fractionated and concentration techniques developed. Similar activity in the same fraction will then be sought in man using the frog skin as an assay system. The first approach will be to test plasma from chronically Na restricted and Na loaded subjects. Once identification of such a factor is made in man this opens up a wide variety of possible approaches in mammals to determine the substance's site of origin, chemical nature, effects on the kidney, mode of regulation and role in human disease states. Initially isovolemic normal and uremic subjects will be contrasted as to levels of this circulating factor. Also, further studies of the nature of the system in the frog will be performed. The relative importance of this system in regulation of Na transport, compared to active Na transport change, will be evaluated. The dependence of the system on the presence of Cl in the adaptive medium will also be assessed. Studies will be made of the nature of the pathway altered in the Cl permeability adaptation.